Metabolic syndrome has become a global epidemic that dramatically increases the risk for type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Elevated hepatic glucose production and lipoprotein secretion contribute to the pathogenesis of hyperglycemia and hyperlipidemia in insulin resistance. Obesity is also associated with excess fat accumulation in the liver, a defining feature of NAFLD that affects both adults and children. While hepatic steatosis often exists as a benign condition with no apparent adverse effects on liver function, progressive liver injury, inflammation, and fibrosis are observed in 20-30% of NAFLD patients with non-alcoholic steatohepatitis (NASH). NASH is emerging as a major risk factor for end-stage liver diseases. The regulatory networks that control hepatic glucose and lipid metabolism have been the focus of research in the past two decades. These studies provide critical insights into the molecular and physiological mechanisms that contribute to glucose and lipid homeostasis. However, hormonal cues that mediate the crosstalk among different tissues, particularly between adipose tissues and the liver, remain poorly defined.
Neuregulins (NRGs) are a family of growth factors that contains a conserved epidermal growth factor (EGF)-like domain. To date, four neuregulin genes (Nrg1-4) have been identified in mammals that generate a diverse array of signaling ligands through extensive alternative splicing. NRGs are typically synthesized as transmembrane proteins that undergo proteolytic cleavage to liberate the extracellular fragments containing the EGF-like domain. Genetic and biochemical studies have demonstrated that NRGs signal through the ErbB family of tyrosine kinase receptors and exert their biological effects in a paracrine, autocrine, and endocrine manner. Nrg1 has been extensively characterized in the development of neuromuscular system, particularly the neuromuscular synapse and the peripheral nerve. In addition, Nrg1 plays an important role in the maintenance of cardiac homeostasis and central nervous system development. Genetic polymorphisms of Nrg1 and Nrg3 have been associated with the risk for schizophrenia and Hirschsprung Disease, respectively. NRGs elicit surprisingly specific biological response in target cells. Nrg4 was discovered based on its sequence homology to other NRG members and was predicted to encode a precursor protein of 115 amino acids. The relevant cellular receptors that mediate the biological effects of Nrg4, particularly on glucose and lipid metabolism and NAFLD, have not been established.
The foregoing observations provide evidence of the continuing need for compositions and formulations useful in treating diseases such as type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD).